20-dimethylamino-pregnenes and their quaternary halides



Patented July 24, 1951 UNITED STATES PATENT OFFICE20-DIMETHYLAMINO-PREGNENES AND THEIR QUATERNARY HALIDES Percy L. Julian,Maywood, and Helen C. Printy and Edwin W. Meyer, Chicago, 111.,assignors to The Glidden Company, Cleveland, Ohio, a corporation of OhioNo Drawing. Application September 11, 1947, Serial No. 773,526

ficient means for the production of therapeutically active materials.Certain of the quaternary ammonium compounds have been found useful insteroid degradation, thus any method for the preparation of the tertiarydimethylamines is of value and, indeed, a method which possesses acertain degree of specificity is of considerable importance.Furthermore, it has been stated that quaternary ammonium halides of7-amino-steroids could not be formed (H. Eckhardt, Ber., 71, 461(1938)), but we have found that all amines studied by our methods haveled to such'quaternary compounds.

It is accordingly an object of, the present invention to provide amethod for the production of tertiary dimethylamines in thesteroidseries.

A further object is to provide a method for the production of quaternaryammonium compounds in the steroid series.

Another-object is to produce quaternary am-' monium compounds fromtertiary dimethylamines of the steroid series.

An additional object is to produce tertiary dimethylamines in thesteroid series.

Still another object is to produce quaternary ammonium compounds in thesteroid series.

Other objects will be apparent to those skilled in the art from thefollowing description.

It has been found that steroid amines containing an amino group eitherat the 17 position of the nucleus or in a group attached to the 17position'of the nucleus may be converted to the dimethylamines byreductive methylation through treatment with formaldehyde and formicacid. Thus, amines of the type where R is thecyclopentanopolyhydrophenane threne nucleus, 3; equals 0 or 1, and.where 1 equals 0 when as equals 0 and where 1/ equals 0, 1 or 2 when asequals 1, may all be readily methylated to compounds of the type l CH3 R(EH (CH2),,N\ I l 2 CH3 above, and, converted to the quaternary ammoniumderivatives of the type where R, x, and y are as previously designatedand where R is alkyl or aralkyl and Z is chlorine, bromine, iodine orhydroxyl. This type of methylation is not sufficiently drastic to causeany extensive or uncertain alteration of other labile functional groups.These dimethylamines may be converted to the quaternary ammonium halidesalts by treatment of the dimethyl tertiary amines with alkyl andaralkyl halides. These quaternary ammonium compounds are valuable in thesynthesis of therapeutically active steroids. The dimethylamines, inaddition to their being useful for'the preparation of the quaternaryammonium compounds, may themselves prove to have valuable therapeuticproperties since 'certain other steroid amines have been recorded in theliterature as being 'bacteriostatic agents. These reactions involved inthe reductivemethylation and formation of the quaternary ammonium saltsmay be illustrated by the following equations, employing typical aminesof the steroid ser1es.

(1) CH: CH3

CH; CH: OHa RAJ-NH: H( N I CH3 CH3 ECHO HCOOH HO lRX CH3 CH HNCH3 CH3(2) CH CH C113 CH3 R N112 N CH3 on, on3

H030 RX HCOOH HO 110- I (3) CH3 I CH3 CH3 CH: I CH3 CH3 $11 I CH3 C I II/OH3 Ac? A3HCE2NH2 AGO CH-CHz-N I AcO 'C'H-CH2.N CH

I l A -CH: R

HOHO v v L I I II ncoon I AC0 I and v (4) CH3 7 CH3 I H3 CH3 (EH3 CH3CH3 CH3' CE; I I

A09 CHCH2 CH2-NH2 AcO H-CHz-OHz-N A09 H-CH'z-CHz-IQ-CHgl l i 0113 f I XR HCHO HCOOH AcO-- AoO- EXAMPLE I with ether and the ether layer waswashed several I times with water and dried. The ethereal .solu'3'hydmmy'5'tamOmhozem/ldlmemylamme tion was concentrated to about 30go. volume, 6.34 g. of 3-hydroxy 5-ternorcholeny1amine was 65 n and thecrystalline Solid separated by m dissolved with gentle Warming in 624 of90% tratlon. A second crop of orystallme materialformic acid. After theaddition of 3.77 g. of 35 was tamed by concentratlon of motheraqueousformaldehyde solution, the mixture was hquor' The P dw refluxed for fourhours. C02 was liberated during nomholenflcllmethylamme' melted at thisperiod The mixture then suspended in 70 Recrystallization from ethergave purer material water-ether and shaken out with dilute hydromeltmgat 1695-17150 v ch'lo'ric acid. The aqueous layer containing sus-EXAMPLE II pended insoluble hydrochloride was separated A andmadealkaline with dilute sodium carbonate3'acetomy'5'temorchqZenyldzmethyzamme solution. The alkaline suspensionwas extracted .75 'A mixture of 3.59 g. of -3-acetoxy-5-ternorch01enylamine, 8.57 g. of 90% formic acid and 35% aqueous formaldehydesolution was heated on the steam bath under reflux for four hours. Themixture was then-chilled, made basic with dilute sodium carbonatesolution and extracted with ether. The ether extract was washed withwater several times and-dried. The white crystalline residue remainingafter removal of solvent was recrystallized from ether-petroleum ether.There resulted 2.1' g., first'crop, of crude 3-acetoxy-5-ternorcholenyldimethylamine. More of the amine may be obtained byconcentration of the mother-liquor. The amine when purified by furtherrecrystallization melts at 1845-1875 C.

EXAMPLE III 3-aeetozcyr-5-ternorcholenyldimethylamine A mixture of 20.5g. of 3-acetoxy-5-ternorcholenylamine acetate, 17.85 g. of 90% formicacid and 35% aqueous formaldehyde was heated on a steam bath for fivehours. Carbon dioxide was liberated at the beginning of the heatingperiod. The mixture was diluted with water. After the addition of etherand dilute hydrochloric acid, the mixture was shaken and the aqueouslayer containing suspended insoluble hydrochloride was separated. Theaqueous suspension was made alkaline with dilute sodium carbonatesolution and extracted with ether. The extract was washed with water anddried. Upon removal of solvent, there remained 17.8 g. of crude3-acetoxy-5-ternorcholenyldimethylamine, M. P. 153- 175 C.Recrystallization from ether gave pure material melting at 184.5-187.5C.

EXAMPLE IV 3-hydromy-5-androstene-17-dimethylamine 25 g. of3-hydroxy-5-androstene-1'7-amine was added with cooling and shaking to24 cc. of 90% formic acid. The slurry became brown. Then 1'7 cc. of35-38% aqueous formaldehyde was added and the mixture was heated forfour hours under reflux on the steam cone. The solid dissolved withcopious evolution of C02. The solution was concentrated in vacuo to athick sirup which was taken up in a mixture of ether and 5% aqueoushydrochloric acid. The acidic layer was made basic with sodium hydroxideand the amine extracted with ether. The ether solution was washedseveral times with water, dried and concentrated to about 150 cc. Afterchilling, the separated solid was filtered and washed with petroleumether. Another crop was obtained from the mother-liquor. There resulted19.0 g. of white crystalline 3-hydroxy-5-androstene-17- dimethylamine,M. P. 208-2l3 C.

EXAMPLE V 3-acetoa:y-allo-ternorcholanyZdimethylamine 1 4.2 g. of3-acetoxy-allo-ternorcholanylamine acetate was mixed with 3 g. of 90%formic acid and 2 g. of 35% aqueous formaldehyde solution and heated ona steam bath for four hours. The solution was then concentrated invacuo, diluted with 5% hydrochloric acid and extracted with ether. Theacidic aqueous layer was made alkaline with 10% sodium hydroxidesolution and extracted with ether. The ether extract was washed withwater and dried. The residue remaining after removal of solvent wascrystallized from benzene. The crude3-acetoxy-allo-ternorcholanyldimethylamine melted at 147-153 C.

EXAMPLE VI 3 (a) ,12 (a) -diaoetoa:y-terncrcholanyldimethylamine Theacid chloride was prepared from 7.2 g.v of 3(a) 12(a)-diacetoxy-bisnor-cholanic acid and 4.2 cc. of thionyl chloride in 20cc. of dry benzene- 40 cc. of dry ether. After one hour the solvent .wasremoved and the acid chloride was dissolved in 130 cc. of acetone. Thissolution was treated, dropwise, at 0-5 C. with a solution of 2.3 g. ofsodium azide in 10 cc. of water. The mixture was stirred for twentyminutes and the azide precipitated by the addition of 200 cc. of coldwater. The solid azide was separated, suspended in 130 cc. of aqueousacetic acid and decomposed by heating to 50'-60 C. for one hour. Theclear solution was steam distilled, neutralized with dilute sodiumcarbonate solution and extracted with ether. The washed and dried ethersolution gave upon concentration 6.2 g. of crude 3(a), 12m) -diacetoxyternorcholanylamine mide derivative, M. P. 220-221" 0.).

The crude amine was methylated by heating 5.2 gpin 6 cc. of formic acidand 4 cc. of 35% aqueous formaldehyde on the steam bath under reflux forfour hours. The orange liquid Was poured into cold dilute sodiumhydroxide and extracted with ether. The ether solution was washed withwater, dried and concentrated in vacuo. The resulting amorphous material(5.5 g.) was crystallized from petroleum ether (B. P. 35-60 C.) yieldingsmall needles of 3(a), 12(a) diacetoxy-ternorcholanyldimethylaminemelting at 134-137 C.

Treatment of the ternorcholanyldimethylamine with methyl iodide inboiling benzene un-- der reflux gave the ether insoluble, solidquaternary methiodide.

EXAMPLE VII A solution of 3.6 g. of 3-keto-5-androstene-l7- amineacetate in 3.6 g. of formic acid and 2.6 g. of 35% aqueous formaldehydewas heated on the steam bath under reflux for four hours. Carbon dioxidewas liberated. The liquid was diluted with sodium carbonate solution andextracted with benzene-chloroform. The extract was washed with waterfollowed by dilute hydrochloric acid. The acidic extract was madealkaline with sodium carbonate solution and extracted withbenzene-chloroform. The extract was then washed with water and dried.Concentration gave the crude 3-keto 5 androstenel -dimethylamine. Thismaterial can be crystallized from ether-petroleum ether (B. P. 35-60 C.)after treatment with activated alumina.

The crude amine gave an ether insoluble quaternary iodide when treatedWith methyl iodide in boiling benzene. It is soluble in water.

EXAIWPLE VIII 3-hydrory- 5-temorchoZenyZtrimethg Zammonium iodide(aceta- 7 EXAMPLE Ix 3ahydrory-5-etiocholenyZtrimethylammonium iodide Asolution of 3.2g. of '3-hydroxy-5-androstenel'l-amine in 90 cc. of drybenzene was treated with 15 cc. of methyl iodide. The mixture wasrefiuxed until it was thick with crystalline solid material. washed withanhydrous ether. The product, B-hydroxy etiocholenyltrimethylammoniumiodide, weighed 4.0 g. Recrystallization from methanol gave 3.5 g. ofpale yellow needles.

EXAMPLE 2 3 -acetory-allo-temo1'ch0Zanyltrimethylammonium bromide .Asolution of 0.5g. of S-acetoxy-allo-ternorcholanyldimethyla-mine in cc.of benzene was mixed with a solution of 5 g. of methyl bromide in 5 cc.of benzene. Themixture was refluxed for five hours. Asheating-progressed the solution became cloudy and then a solidseparated. After dilution with ether, the white solid was separated andwashed well with ether. The product, 3 acetoxy alloternorcholanyltrimethyl ammonium bromide, weighed 0.4.- g. The materialis quite soluble in methanol but may be recrystallized from a cold,concentrated solution.

EXAMPLE XII 3-acetoscy-5-temorcholenyldimethylbeneylammonium chloride Asolution of 1.0 .g. of 3 acetoxy 5 ternorcholenyldimethylamine in.10 cc.of benzylchloride was refluxed for minutes. The chilled mixture wasdiluted with ether and the white solid was filtered. This material, 0.4g., was quite soluble in methanol but almost insoluble in ether. It isrecrystallized from ether-methanol.

The fine crystals of 3-acetoxy-5-ternorcholenyldimethylbenzylammoniumchloride decomposed slightly when heated to 285 C. but did .not melt.They proved to be partially soluble in water; the aqueous solutionforming a white precipitate upon the addition of silver nitratesolution.

EXAMPLE XIII 3m micry-5-eticcholenyldimethylisoamylammonium bromide Asolution of 1.0 g. of 3-hydroxy-5-androstenel7-dimethylamine in 10 cc.of isoamyl bromide was refluxed for one hour. After chilling the mixturewas diluted with ether and the solid was filtered. The crystallinesolid, 0.5 g., was poorly soluble in ether and slightly soluble inwater. It may be recrystallized from methanol. This material, 3 hydroxy5 etiocholenyldimethyl isoaznylammonium bromide does not meet below 250C.

After chilling, the solid was filtered and a EXAMPLE EV 3 (a) ,12 (a)-diaceto.'z:y-bisnorch'olanyldimethylamine I "The acid chloride wasprepared from 9.2 gfoi treated at 10 C. with a solution of 2.8 g.sodium.

azide .12 cc. Water, added dropwise in 10 minutes. The azidewasprecipitated with 300cc. cold water as a gum, which was extracted withalcohol-free ether. The ethereal solution was washed, dried,concentrated in vacuo. The residual solid was dissolved in 160 cc.acetic acid and decomposed byheating one hour :at 15Dil0 .F. Thesolutionwas steam distilled, made alkaline with vsodiumcarbonate, extracted withether, and theethereal solution ashaken out with.10% hydrochloric acid.The acid washes were made alkaline with sodium carbonate solution,.theamine extracted with ether, washed, and dried. On concentration 8.0 "g.amine was obtained (acetamide derivative M. .P. 215 0.).

Thecrude amine was methylated by heating 8.0 g, .in.8 cc.formic'acid'and 6 00. 38% aqueous formaldehyde'ior- 4 hours under refluxon the steambath. Thesolution was diluted with water. and 5 hydrochloricacid, shaken out with ether, and the water layer madealkaline with 5%sodium hydroxide. The white precipitate was extracted with ether,washed, dried, concentrated and crystallized from ether-petroleum ether(B. P. 35-60 C.). A total of 5.7 g. amine was obtained. Onrecrystallization from ether it melted at 108-171" C.

A 2.6 g. sample of the dimethylamine was dissclvedinSO cc. of benzeneand treated with 5 cc. of methyliodide. After refluxing for one-halfhour, the -quaternary -halide, 3(a),- 1'20)- diaoetoxybisnorcholanyltrimethylammoniu-m iodide, was precipitated by theaddition of ether.

-, The-mixture was chilled,filtered and the solid washed with ether. Thecrude quaternary 1ammoniu-m iodide weighed 3. 4 g.

EXAMPLE EJI 301) .12 0) -diucetorymorchoianylzfimethyiamine :The*diacetoxyderivative from 20:0. g'. of desoxych-oiic acid was convertedto the acid chloride with 13 cc. of thionyl chloride-in cc. of .drybenezene-ZOO cc. of dry -ether,and one :drop 10% pyridine in benzene.After one and onehalf hours the solvent was removed in vacuo and thecrystalline acid chlorideidissolved in 400 cc. of distilled acetone.This solution was cooled to 5 C. and a solution containing 7.0 g. orsodium azide in 30 cc. of distilled water was added during 30 minutes.The reaction was stirred for 30 minutes, then diluted with 600 cc. ofcold water, added during one hour. Theprecipitated azide was filteredand washed with water. The moist aside was decomposed in 400 cc. 80%acetic acid at 70 C. for one hour, then steam distilled for 45 minutes.The reaction was made slightly alkaline with sodium carbonate andextracted with ether. The ethereal extract was washed, shaken out with10% hydrochloric acid; the acid washes were "made alkaline withsodiumcar'oonate, extracted with ether, washed, dried, and concentrated.15.7 g. of amine portion was obtained,

9 This crystallized from ether-petroleum-ether (B. P. 35-60 C.) asneedles, M. P. 156-158 C.

20 g. of the crude amine was methylated in 20 cc. of 90% formic acid and15 cc. of 38% aqueous formaldehyde by warming on the steam bath, underreflux, for sixteen hours. The reaction was diluted with water, pouredwith stirring into sodium carbonate solution and the amorphous solidfiltered and washed. It was taken up in ether, the amine shaken out with10% hydrochloric acid, and the acid washes made alkaline with sodiumcarbonate. The amine was extracted with ether, washed, dried, andconcentrated. The residue Weighed 15.5 g. This material was dissolved in100 cc. of methanol, 50 g. of methyl iodide added, and the solutionrefluxed for two hours. It was then concentrated, dry ether added, and12.3 g. of methiodide was obtained as yellow crystals. Onrecrystallization this melted at 218-220 C.

The foregoing examples are illustrative of the invention, it beingunderstood that various changes and modifications may be made thereinwithout departing from the spirit and the scope of the invention. Thus,other alkyl and aralkyl iodides, bromides and chlorides may be used forthe preparation of the quaternary halides.

10 Reference is made herein to the copending application of two of us,Serial No. 770,336, filed August 23, 1947. 7

Having described the invention, what is claimed is: l. Pregnenecompounds selected from the class consisting of20-dimethy1amino-5-pregnenes and their quaternary ammonium halides otherthan quaternary ammonium fluorides.

2. The quaternary ammonium halide compounds of claim 1.

3.v The trimethyl ammonium halides of claim 2. 4.20-dimethylamino-5-pregnenes. 5. 3-acetoxy-20-dimethylamino-5-pregnene.

PERCY L. JULIAN. HELEN C. PRINTY. EDWIN W. MEYER.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,252,863 Raymond et al Aug. 19,1941 2,481,524 MacPhillamy Sept. 13, 1949

1. PREGNENE COMPOUNDS SELECTED FROM THE CLASS CONSISTING OF2-DIMETHYLAMINO-5-PREGNENES AND THEIR QUATERNARY AMMONIUM HALIDES OTHERTHAN QUATERNARY AMMONIUM FLUORIDES.